Tumor-associated macrophages (TAMs) contribute substantially to the tumor mass of gliomas and have been shown to play a major role in the creation of a tumor microenvironment that promotes tumor progression. Shortcomings of attempts at antiglioma immunotherapy may result from a failure to adequately address these effects. Emerging evidence supports an independent categorization of glioma TAMs as alternatively activated M2-type macrophages, in contrast to classically activated proinflammatory M1-type macrophages. These M2-type macrophages exert glioma-supportive effects through reduced anti-tumor functions, increased expression of immunosuppressive mediators, and nonimmune tumor promotion through expression of trophic and invasion-facilitating substances. Much of our work has demonstrated these features of glioma TAMs, and together with the supporting literature will be reviewed here. Additionally, the dynamics of glioma cell-TAM interaction over the course of tumor development remain poorly understood; our efforts to elucidate glioma cell-TAM dynamics are summarized. Finally, the molecular pathways which underlie M2-type TAM polarization and gene expression similarly require further investigation, and may present the most potent targets for immunotherapeutic intervention. Highlighting recent evidence implicating the transcription factor STAT3 in immunosuppressive tumorigenic glioma TAMs, we advocate for gene array-based approaches to identify yet unappreciated expression regulators and effector molecules important to M2-type glioma TAMs polarization and function within the glioma tumor microenvironment. 1. Introduction Malignant glioma is uniformly fatal with a median survival of less than 15 months with aggressive treatment [1]. Advances in surgical, radiation, and conventional chemotherapeutic therapies have had minimal impact on the prognosis of this aggressive disease [1]. The recalcitrance of malignant glioma to standard therapies is believed to result from phenotypic heterogeneity and diffuse infiltration into normal brain parenchyma [2], as well as residence within the unique immune environment of the central nervous system (CNS) [3]. Long viewed as an “immune-privileged” site due to a perceived lack of specialized antigen presenting cells (APCs), restriction from circulating lymphocytes and other immune mediators by the blood brain barrier (BBB), and absence of lymphatic drainage [4], the CNS appeared to possess little immunologic potential to resist glioma progression. Evidence accumulated over the last 20 years, however, has largely debunked
References
[1]
H. Ohgaki and P. Kleihues, “Epidemiology and etiology of gliomas,” Acta Neuropathologica, vol. 109, no. 1, pp. 93–108, 2005.
[2]
E. C. Holland, “Glioblastoma multiforme: the terminator,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 12, pp. 6242–6244, 2000.
[3]
B. D. Choi, K. S. Chen, and J. H. Sampson, “Tumors of the central nervous system,” in Tumors of the Central Nervous System, M. A. Hayat, Ed., vol. 1, Springer, Dordrecht, The Netherlands, 2011.
[4]
Z. Fabry, C. S. Raine, and M. N. Hart, “Nervous tissue as an immune compartment: the dialect of the immune response in the CNS,” Immunology Today, vol. 15, no. 5, pp. 218–224, 1994.
[5]
C. J. Harling-Berg, J. J. Hallett, J. T. Park, and P. M. Knopf, “Hierarchy of immune responses to antigen in the normal brain,” Current Topics in Microbiology and Immunology, vol. 265, pp. 1–22, 2002.
[6]
J. Gehrmann, R. B. Banati, C. Wiessner, K. A. Hossmann, and G. W. Kreutzberg, “Reactive microglia in cerebral ischaemia: an early mediator of tissue damage?” Neuropathology and Applied Neurobiology, vol. 21, no. 4, pp. 277–289, 1995.
[7]
W. F. Hickey and H. Kimura, “Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo,” Science, vol. 239, no. 4837, pp. 290–292, 1988.
[8]
R. Beschorner, T. D. Nguyen, F. G？zalan et al., “CD14 expression by activated parenchymal microglia/macrophages and infiltrating monocytes following human traumatic brain injury,” Acta Neuropathologica, vol. 103, no. 6, pp. 541–549, 2002.
[9]
T. Owens, T. Renno, V. Taupin, and M. Krakowski, “Inflammatory cytokines in the brain: does the CNS shape immune responses?” Immunology Today, vol. 15, no. 12, pp. 566–571, 1994.
[10]
E. Ulvestad, K. Williams, R. Bjerkvig, K. Tiekotter, J. Antel, and R. Matre, “Human microglial cells have phenotypic and functional characteristics in common with both macrophages and dendritic antigen-presenting cells,” Journal of Leukocyte Biology, vol. 56, no. 6, pp. 732–740, 1994.
[11]
K. Williams Jr., E. Ulvestad, L. Cragg, M. Blain, and J. P. Antel, “Induction of primary T cell responses by human glial cells,” Journal of Neuroscience Research, vol. 36, no. 4, pp. 382–390, 1993.
[12]
S. Miescher, T. L. Whiteside, N. de Tribolet, and V. von Fliedner, “In situ characterization, clonogenic potential, and antitumor cytolytic activity of T lymphocytes infiltrating human brain cancers,” Journal of Neurosurgery, vol. 68, no. 3, pp. 438–448, 1988.
[13]
A. B. Heimberger and J. H. Sampson, “Immunotherapy coming of age: what will it take to make it standard of care for glioblastoma?” Neuro-Oncology, vol. 13, no. 1, pp. 3–13, 2011.
[14]
E. J. Small, P. F. Schellhammer, C. S. Higano et al., “Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer,” Journal of Clinical Oncology, vol. 24, no. 19, pp. 3089–3094, 2006.
[15]
F. S. Hodi, S. J. O’Day, D. F. McDermott, et al., “Improved survival with ipilimumab in patients with metastatic melanoma,” The New England Journal of Medicine, vol. 363, no. 8, pp. 711–723, 2010.
[16]
R. Yamanaka, “Cell- and peptide-based immunotherapeutic approaches for glioma,” Trends in Molecular Medicine, vol. 14, no. 5, pp. 228–235, 2008.
[17]
M. C. Kuppner, M. F. Hamou, and N. de Tribolet, “Immunohistological and functional analyses of lymphoid infiltrates in human glioblastomas,” Cancer Research, vol. 48, no. 23, pp. 6926–6932, 1988.
[18]
D. A. Mitchell, P. E. Fecci, and J. H. Sampson, “Immunotherapy of malignant brain tumors,” Immunological Reviews, vol. 222, no. 1, pp. 70–100, 2008.
[19]
B. Badie and J. Schartner, “Role of microglia in glioma biology,” Microscopy Research and Technique, vol. 54, no. 2, pp. 106–113, 2001.
[20]
A. M. Kostianovsky, L. M. Maier, R. C. Anderson, J. N. Bruce, and D. E. Anderson, “Astrocytic regulation of human monocytic/microglial activation,” Journal of Immunology, vol. 181, no. 8, pp. 5425–5432, 2008.
[21]
B. C. Kennedy, L. M. Maie, R. D. 'Amico, ", et al., “Dynamics of central and peripheral immunomodulation in a murine glioma model,” BMC Immunology, vol. 10, article 11, 2009.
[22]
D. S. Markovic, R. Glass, M. Synowitz, N. van Rooijen, and H. Kettenmann, “Microglia stimulate the invasiveness of glioma cells by increasing the activity of metalloprotease-2,” Journal of Neuropathology and Experimental Neurology, vol. 64, no. 9, pp. 754–762, 2005.
[23]
J. J. Watters, J. M. Schartner, and B. Badie, “Microglia function in brain tumors,” Journal of Neuroscience Research, vol. 81, no. 3, pp. 447–455, 2005.
[24]
H. Zhai, F. L. Heppner, and S. E. Tsirka, “Microglia/macrophages promote glioma progression,” Glia, vol. 59, no. 3, pp. 472–485, 2011.
[25]
G. C. Daginakatte and D. H. Gutmann, “Neurofibromatosis-1 (Nf1) heterozygous brain microglia elaborate paracrine factors that promote Nf1-deficient astrocyte and glioma growth,” Human Molecular Genetics, vol. 16, no. 9, pp. 1098–1112, 2007.
[26]
A. Wesolowska, A. Kwiatkowska, L. Slomnicki et al., “Microglia-derived TGF-β as an important regulator of glioblastoma invasion—an inhibition of TGF-β-dependent effects by shRNA against human TGF-β type II receptor,” Oncogene, vol. 27, no. 7, pp. 918–930, 2008.
[27]
S. Wagner, S. Czub, M. Greif et al., “Microglial/macrophage expression of interleukin 10 in human glioblastomas,” International Journal of Cancer, vol. 82, no. 1, pp. 12–16, 1999.
[28]
W. Penfield, “Microglia and the process of phagocytosis in gliomas,” The American Journal of Pathology, vol. 1, no. 1, pp. 77–97, 1925.
[29]
W. Li and M. B. Graeber, “The molecular profile of microglia under the influence of glioma,” Neuro-Oncology, vol. 14, no. 8, pp. 958–978, 2012.
[30]
J. MacMicking, Q. W. Xie, and C. Nathan, “Nitric oxide and macrophage function,” Annual Review of Immunology, vol. 15, pp. 323–350, 1997.
[31]
U. Boehm, T. Klamp, M. Groot, and J. C. Howard, “Cellular responses to interferon-gamma.,” Annual Review of Immunology, vol. 15, pp. 749–795, 1997.
[32]
S. F. Hussain, D. Yang, D. Suki, E. Grimm, and A. B. Heimberger, “Innate immune functions of microglia isolated from human glioma patients,” Journal of Translational Medicine, vol. 4, article 15, 2006.
[33]
P. Filipazzi, V. Huber, and L. Rivoltini, “Phenotype, function and clinical implications of myeloid-derived suppressor cells in cancer patients,” Cancer Immunology, Immunotherapy, vol. 61, no. 2, pp. 255–263, 2012.
[34]
C. Huettner, S. Czub, S. Kerkau, W. Roggendorf, and J. C. Tonn, “Interleukin 10 is expressed in human gliomas in vivo and increases glioma cell proliferation and motility in vitro,” Anticancer Research, vol. 17, no. 5 A, pp. 3217–3224, 1997.
[35]
I. F. Parney, “Basic concepts in glioma immunology,” Advances in Experimental Medicine and Biology, vol. 746, pp. 42–52, 2012.
[36]
D. Hanahan and R. A. Weinberg, “Hallmarks of cancer: the next generation,” Cell, vol. 144, no. 5, pp. 646–674, 2011.
[37]
E. A. Ling and W. C. Wong, “The origin and nature of ramified and amoeboid microglia: a historical review and current concepts,” Glia, vol. 7, no. 1, pp. 9–18, 1993.
[38]
F. Ginhoux, M. Greter, M. Leboeuf et al., “Fate mapping analysis reveals that adult microglia derive from primitive macrophages,” Science, vol. 330, no. 6005, pp. 841–845, 2010.
[39]
T. Morioka, T. Baba, K. L. Black, and W. J. Streit, “Inflammatory cell infiltrates vary in experimental primary and metastatic brain tumors,” Neurosurgery, vol. 30, no. 6, pp. 891–896, 1992.
[40]
R. A. Morantz, G. W. Wood, M. Foster, M. Clark, and K. Gollahon, “Macrophages in experimental and human brain tumors—part 2: studies of the macrophage content of human brain tumors,” Journal of Neurosurgery, vol. 50, no. 3, pp. 305–311, 1979.
[41]
K. L. Lambertsen, B. H. Clausen, A. A. Babcock et al., “Microglia protect neurons against ischemia by synthesis of tumor necrosis factor,” Journal of Neuroscience, vol. 29, no. 5, pp. 1319–1330, 2009.
[42]
J. Priller, A. Flügel, T. Wehner et al., “Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment,” Nature Medicine, vol. 7, no. 12, pp. 1356–1361, 2001.
[43]
A. Flgel, M. Bradl, G. W. Kreutzberg, and M. B. Graeber, “Transformation of donor-derived bone marrow precursors into host microglia during autoimmune CNS inflammation and during the retrograde response to axotomy,” Journal of Neuroscience Research, vol. 66, no. 1, pp. 74–82, 2001.
[44]
M. Rodriguez, L. Alvarez-Erviti, F. J. Blesa et al., “Bone-marrow-derived cell differentiation into microglia: a study in a progressive mouse model of Parkinson's disease,” Neurobiology of Disease, vol. 28, no. 3, pp. 316–325, 2007.
[45]
A. R. Simard, D. Soulet, G. Gowing, J. P. Julien, and S. Rivest, “Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease,” Neuron, vol. 49, no. 4, pp. 489–502, 2006.
[46]
W. AlShakweer, Y. Alwelaie, A. M. Mankung, and M. B. Graeber, “Bone marrow-derived microglia in pilocytic astrocytoma,” Frontiers in Bioscience (Elite Edition), vol. 3, pp. 371–379, 2011.
[47]
B. Badie and J. M. Schartner, “Flow cytometric characterization of tumor-associated macrophages in experimental gliomas,” Neurosurgery, vol. 46, no. 4, pp. 957–962, 2000.
[48]
D. Germain and D. A. Frank, “Targeting the cytoplasmic and nuclear functions of signal transducers and activators of transcription 3 for cancer therapy,” Clinical Cancer Research, vol. 13, no. 19, pp. 5665–5669, 2007.
[49]
J. C. Rodrigues, G. C. Gonzalez, L. Zhang et al., “Normal human monocytes exposed to glioma cells acquire myeloid-derived suppressor cell-like properties,” Neuro-Oncology, vol. 12, no. 4, pp. 351–365, 2010.
[50]
J. M. Schartner, A. R. Hagar, M. van Handel, L. Zhang, N. Nadkarni, and B. Badie, “Impaired capacity for upregulation of MHC class II in tumor-associated microglia,” Glia, vol. 51, no. 4, pp. 279–285, 2005.
[51]
T. Hirano, K. Ishihara, and M. Hibi, “Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors,” Oncogene, vol. 19, no. 21, pp. 2548–2556, 2000.
[52]
E. C. Brantley and E. N. Benveniste, “Signal transducer and activator of transcription-3: a molecular hub for signaling pathways in gliomas,” Molecular Cancer Research, vol. 6, no. 5, pp. 675–684, 2008.
[53]
T. Jansen, B. Tyler, J. L. Mankowski et al., “FasL gene knock-down therapy enhances the antiglioma immune response,” Neuro-Oncology, vol. 12, no. 5, pp. 482–489, 2010.
[54]
V. V. Didenko, H. N. Ngo, C. Minchew, and D. S. Baskin, “Apoptosis of T lymphocytes invading glioblastomas multiforme: a possible tumor defense mechanism,” Journal of Neurosurgery, vol. 96, no. 3, pp. 580–584, 2002.
[55]
A. L. Ford, E. Foulcher, F. A. Lemckert, and J. D. Sedgwick, “Microglia induce CD4 T lymphocyte final effector function and death,” Journal of Experimental Medicine, vol. 184, no. 5, pp. 1737–1745, 1996.
[56]
A. L. Ford, E. Foulcher, F. A. Lemckert, and J. D. Sedgwick, “Microglia induce CD4T lymphocyte final effector function and death,” Journal of Experimental Medicine, vol. 184, no. 5, pp. 1737–1745, 1996.
[57]
B. Badie, J. Schartner, S. Prabakaran, J. Paul, and J. Vorpahl, “Expression of Fas ligand by microglia: possible role in glioma immune evasion,” Journal of Neuroimmunology, vol. 120, no. 1-2, pp. 19–24, 2001.
[58]
S. Wintterle, B. Schreiner, M. Mitsdoerffer et al., “Expression of the B7-related molecule B7-H1 by glioma cells: a potential mechanism of immune paralysis,” Cancer Research, vol. 63, no. 21, pp. 7462–7467, 2003.
[59]
A. T. Parsa, J. S. Waldron, A. Panner et al., “Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma,” Nature Medicine, vol. 13, no. 1, pp. 84–88, 2007.
[60]
V. Samuels, J. M. Barrett, S. Bockman, C. G. Pantazis, and M. B. Allen, “Immunocytochemical study of transforming growth factor expression in benign and malignant gliomas,” The American Journal of Pathology, vol. 134, no. 4, pp. 895–902, 1989.
[61]
B. Badie, J. Schartner, J. Klaver, and J. Vorpahl, “In vitro modulation of microglia motility by glioma cells is mediated by hepatocyte growth factor/scatter factor,” Neurosurgery, vol. 44, no. 5, pp. 1077–1083, 1999.
[62]
J. C. Tsai, C. K. Goldman, and G. Y. Gillespie, “Vascular endothelial growth factor in human glioma cell lines: induced secretion by EGF, PDGF-BB, and bFGF,” Journal of Neurosurgery, vol. 82, no. 5, pp. 864–873, 1995.
[63]
C. Kjellman, S. P. Olofsson, O. Hansson et al., “Expression of TGF-β isoforms, TGF-β receptors, and SMAD molecules at different stages of human glioma,” International Journal of Cancer, vol. 89, no. 3, pp. 251–258, 2000.
[64]
S. Bodmer, K. Strommer, K. Frei et al., “Immunosuppression and transforming growth factor-β in glioblastoma. Preferential production of transforming growth factor-β2,” Journal of Immunology, vol. 143, no. 10, pp. 3222–3229, 1989.
[65]
A. Wu, J. Wei, L. Y. Kong et al., “Glioma cancer stem cells induce immunosuppressive macrophages/microglia,” Neuro-Oncology, vol. 12, no. 11, pp. 1113–1125, 2010.
[66]
S. Koochekpour, A. Merzak, and G. J. Pilkington, “Vascular endothelial growth factor production is stimulated by gangliosides and TGF-β isoforms in human glioma cells in vitro,” Cancer Letters, vol. 102, no. 1-2, pp. 209–215, 1996.
[67]
W. Wick, M. Platten, and M. Weller, “Glioma cell invasion: regulation of metalloproteinase activity by TGF-β,” Journal of Neuro-Oncology, vol. 53, no. 2, pp. 177–185, 2001.
[68]
R. Kiefer, R. Gold, J. Gehrmann, D. Lindholm, H. Wekerle, and G. W. Kreutzberg, “Transforming growth factor β expression in reactive spinal cord microglia and meningeal inflammatory cells during experimental allergic neuritis,” Journal of Neuroscience Research, vol. 36, no. 4, pp. 391–398, 1993.
[69]
D. Lindholm, E. Castren, R. Kiefer, F. Zafra, and H. Thoenen, “Transforming growth factor-β1 in the rat brain: increase after injury and inhibition of astrocyte proliferation,” Journal of Cell Biology, vol. 117, no. 2, pp. 395–400, 1992.
[70]
R. Kiefer, M. L. Supler, K. V. Toyka, and W. J. Streit, “In situ detection of transforming growth factor-β mRNA in experimental rat glioma and reactive glial cells,” Neuroscience Letters, vol. 166, no. 2, pp. 161–164, 1994.
[71]
E. A. Maher, F. B. Furnari, R. M. Bachoo et al., “Malignant glioma: genetics and biology of a grave matter,” Genes and Development, vol. 15, no. 11, pp. 1311–1333, 2001.
[72]
C. Nolte, F. Kirchhoff, and H. Kettenmann, “Epidermal growth factor is a motility factor for microglial cells in vitro: evidence for EGF receptor expression,” European Journal of Neuroscience, vol. 9, no. 8, pp. 1690–1698, 1997.
[73]
S. J. Coniglio, E. Eugenin, K. Dobrenis et al., “Microglial stimulation of glioblastoma invasion involves EGFR and CSF-1R signaling,” Molecular Medicine, vol. 18, pp. 519–527, 2012.
[74]
S. Koochekpour, M. Jeffers, S. Rulong et al., “Met and hepatocyte growth factor/scatter factor expression in human gliomas,” Cancer Research, vol. 57, no. 23, pp. 5391–5398, 1997.
[75]
P. Kunkel, S. Müller, P. Schirmacher et al., “Expression and localization of scatter factor/hepatocyte growth factor in human astrocytomas,” Neuro-Oncology, vol. 3, no. 2, pp. 82–88, 2001.
[76]
J. Laterra, M. Nam, E. Rosen et al., “Scatter factor/hepatocyte growth factor gene transfer enhances glioma growth and angiogenesis in vivo,” Laboratory Investigation, vol. 76, no. 4, pp. 565–577, 1997.
[77]
C. Eckerich, S. Zapf, R. Fillbrandt, S. Loges, M. Westphal, and K. Lamszus, “Hypoxia can induce c-Met expression in glioma cells and enhance SF/HGF-induced cell migration,” International Journal of Cancer, vol. 121, no. 2, pp. 276–283, 2007.
[78]
C. Sheng-Hua, M. Yan-Bin, Z. Zhi-An et al., “Radiation-enhanced hepatocyte growth factor secretion in malignant glioma cell lines,” Surgical Neurology, vol. 68, no. 6, pp. 610–613, 2007.
[79]
A. Waziri, B. Killory, A. T. Ogden III et al., “Preferential in situ CD4+CD56+ T cell activation and expansion within human glioblastoma,” Journal of Immunology, vol. 180, no. 11, pp. 7673–7680, 2008.
[80]
A. El Andaloussi and M. S. Lesniak, “An increase in CD4+CD25+FOXP3+ regulatory T cells in tumor-infiltrating lymphocytes of human glioblastoma multiforme,” Neuro-Oncology, vol. 8, no. 3, pp. 234–243, 2006.
[81]
P. E. Fecci, D. A. Mitchell, J. F. Whitesides et al., “Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma,” Cancer Research, vol. 66, no. 6, pp. 3294–3302, 2006.
[82]
H. Ohgaki and P. Kleihues, “The definition of primary and secondary glioblastoma,” Clinical Cancer Research, vol. 19, no. 4, pp. 764–772, 2013.
[83]
M. Mizoguchi, R. A. Betensky, T. T. Batchelor, D. C. Bernay, D. N. Louis, and C. L. Nutt, “Activation of STAT3, MAPK, and AKT in malignant astrocytic gliomas: correlation with EGFR status, tumor grade, and survival,” Journal of Neuropathology and Experimental Neurology, vol. 65, no. 12, pp. 1181–1188, 2006.
[84]
L. Zhang, D. Alizadeh, M. van Handel, M. Kortylewski, H. Yu, and B. Badie, “Stat3 inhibition activates tumor macrophages and abrogates glioma growth in mice,” Glia, vol. 57, no. 13, pp. 1458–1467, 2009.
[85]
L. K. Schaefer, D. G. Menter, and T. S. Schaefer, “Activation of Stat3 and Stat1 DNA binding and transcriptional activity in human brain tumour cell lines by gp130 cytokines,” Cellular Signalling, vol. 12, no. 3, pp. 143–151, 2000.
[86]
M. Kortylewski, M. Kujawski, T. Wang et al., “Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity,” Nature Medicine, vol. 11, no. 12, pp. 1314–1321, 2005.
